Preservative system for topically administrable pharmaceutical compositions containing a fatty acid/amino acid soap

ABSTRACT

Fatty acid/amino acid soaps are used in conjunction with an antifungal acid and a chelating agent as a new preservative system for topically administrable pharmaceutical compositions.

This application claims priority from co-pending U.S. provisionalapplication, Ser. No. 60/105,819, filed Oct. 27, 1998.

BACKGROUND OF THE INVENTION

The present invention relates generally to the preservation ofpharmaceutical compositions. In particular, the present inventionrelates to the use of certain fatty acid/amino acid soaps in combinationwith an antifungal acid and a chelating agent as a preservative systemfor topically administrable pharmaceutical compositions.

Multi-dose pharmaceutical products, particularly those intended fortopical administration to the eyes, nose or ears, often contain or arerequired to contain a preservative. Such products are sterilized whenmanufactured, but contain preservatives to prevent or inhibit microbialgrowth in the event they are contaminated during use. The most commonpreservatives for topical, multi-dose ophthalmic products are quaternaryammonium preservatives, such as benzalkonium chloride andpolyquaternium-1. Other known preservatives for topical, multi-doseophthalmic products are chlorobutanol; chlorhexidine; parabens; andthimerosal (though thimerosal is not as common as it used to be, due toregulatory and environmental concerns related to the fact it containsmercury).

In some instances, preservatives alone are insufficient to meetregulatory standards for preservative efficacy. In such cases,preservative aids or adjuncts are used. Examples of preservativeenhancing additives include EDTA (edetate disodium) and boric acid.Additional examples of preservative enhancing additives include certainsarcosinate and lactylate surfactants.

U.S. Pat. No. 5,520,920 (Castillo, et al.) discloses the use of certainmodified sarcosinates and lactylates to enhance antimicrobialeffectiveness of ophthalmic compositions, particularly in the case wherecationic preservatives otherwise bind to anionic polyelectrolytes.Representative modified sarcosinates include those sold under theHamposyl® trade name, such as lauroyl sarcosine (Hamposyl® L), oleoylsarcosine (Hamposyl ® O), myrstoyl sarcosine (Hamposyl® M), cocoylsarcosine (Hamposyl® C), stearoyl sarcosine (Hamposyl® S), andpelargodoyl sarcosine (Hamposyl® P). Representative lactylates includesodium capryl lactylate (Pationic® 122A).

Fatty acid/amino acid soaps are known and include, for example, thosesurfactants sold under the Aminosoap® trade name (Ajinomoto Co., Inc.,Tokyo, Japan). According to product brochures, Aminosoap® surfactantsare used in hair and body care (hair shampoo, body wash and bath foam),facial care (facial cleanser, facial washing foam, facial washing crbme,and make-up remover), and household and health care.

Alternative preservative systems for topically administrablepharmaceutical compositions are desired, especially in those instanceswhen conventional preservatives, such as benzalkonium chloride, areincompatible with other ingredients in the composition.

SUMMARY OF THE INVENTION

The present invention provides a preservative system for topicallyadministrable pharmaceutical compositions. The preservative systemconsists essentially of one or more fatty acid/amino acid soaps, one ormore pharmaceutically acceptable antifungal acids and one or morepharmaceutically acceptable chelating agents. According to the presentinvention, topically administrable pharmaceutical compositions arepreserved without the need for a conventional preservative ingredient.Thus, the compositions of the present invention do not contain anypreservatives selected from the group consisting of quaternary ammoniumpreservatives, such as benzalkonium chloride, benzalkonium bromide, andpolyquaternium-1; chlorhexidine; chlorobutanol; cetylpyridiniumchloride; parabens; and thimerosal.

The present invention also relates to a method of preserving a topicallyadministrable pharmaceutical composition, wherein the method comprisesadding the preservative system described above to such composition.

Among other factors, the present invention is based on the finding thattopically administrable pharmaceutical compositions can be preservedusing a preservative system consisting of one or more fatty acid/aminoacid soaps, one or more pharmaceutically acceptable antifungal acids andone or more pharmaceutically acceptable chelating agents, without theneed for a conventional preservative ingredient.

DETAILED DESCRIPTION OF THE INVENTION

Unless indicated otherwise, all amounts of composition ingredientsexpressed in percentage terms are expressed as weight/weight.

Fatty acid/amino acid soaps useful in the preservative systems of thepresent invention are those wherein the fatty acid component is derivedfrom a C₈-C₂₄ fatty acid and the amino acid component is selected fromthe group consisting of lysine and arginine. Preferably, the fatty acidcomponent is selected from the group consisting of cocoyl, linoleoyl,lauroyl, myristoyl, stearoyl, oleoyl, and pelargodoyl fatty acidresidues. Such fatty acid/amino acid soaps are commercially available orcan be made by known methods. For example, the soap where the fatty acidcomponent is cocoyl and the amino acid component is derived fromarginine is commercially available as AMINOSOAP AR-12 from AjinomotoCo., Inc. (Tokyo, Japan). The soap where the fatty acid component iscocoyl and the amino acid component is derived from lysine is availableas AMINOSOAP LYC-12.

In general, the amount of fatty acid/amino acid soap present in thecompositions of the present invention is from about 0.001 to about 1%,preferably from about 0.01 to about 0.2%, and most preferably from about0.03 to about 0.12%. For topical ophthalmic preparations, theconcentration of the fatty acid/amino acid soap should not be so highthat it causes severe discomfort.

The preservative systems of the present invention also contain one ormore pharmaceutically acceptable antifungal acids selected from thegroup consisting of boric acid; benzoic acid; salicylic acid; sorbicacid; lactic acid; acetic acid; and pharmaceutically acceptable saltsthereof. Boric acid is the most preferred antifungal acid. In general,the amount of antifungal acid present in the compositions of the presentinvention is from about 0.01 to about 1%, preferably about 0.1 to about0.6%, and most preferably from about 0.3 to about 0.4%. The antifungalacid component can be added to pharmaceutical compositions in the formof a pharmaceutically acceptable salt.

In addition to the fatty acid/amino acid soap(s) and antifungal acid(s),the preservative system contains one or more pharmaceutically acceptablechelating agents. Such chelating agents are selected from thegroup_consisting of EDTA; ethylene glycol-bis-(b-aminoehtylether)N,N,N′,N′-tetraacetic acid (EGTA);1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA);ethylene-N,N′-diglycine (EDDA); 2,2′-(ethylendiimino)-dibutyric acid(EDBA); and pharmaceutically acceptable salts thereof. The mostpreferred chelating agent is EDTA. The chelating agents can be added topharmaceutical compositions in the form of a pharmaceutically acceptablesalt. For example, EDTA may be added in the form of edetate disodium. Ingeneral, the amount of chelating agent present in the compositions ofthe present invention is from about 0.001 to about 1%, preferably about0.01 to about 0.2%, and most preferably about 0.01 to about 0.1%.

The preservative system of the present invention can be used in alltypes of topically administrable pharmaceutical compositions (e.g.,solutions, suspensions, emulsions, gels), but is preferably used fortopically administrable ophthalmic, otic, nasal or dermal compositions.Most preferred are topically administrable ophthalmic or oticcompositions.

The topically administrable pharmaceutical compositions of the presentinvention optionally comprise, in addition to the preservative systemdescribed above, conventional ingredients, provided that thecompositions do not contain a conventional preservative. For example,the compositions of the present invention may contain one or more activeingredients (though, in some instances, such as in the case of dry eyeproducts, no drug will be present). Other optional ingredients include,but are not limited to, pharmaceutically acceptable buffers, tonicityagents, drug carriers, sustained-release agents, viscosity modifyingagents, comfort-enhancing agents, solubilizing aids, pH adjustingagents, antioxidants and other stabilizing agents.

The active ingredient or ingredients that can be included in thecompositions of the present invention include all ophthalmic,dermatological, otic or nasal agents that can be topically applied. Forexample, such ophthalmic agents include (but are not limited to):anti-glaucoma agents, such as beta-blockers (e.g., betaxolol andtimolol), muscarinics (e.g., pilocarpine), prostaglandins, carbonicanhydrase inhibitors (e.g., acetazolamide, methazolamide andethoxzolamide), dopaminergic agonists and antagonists, and alphaadrenergic receptor agonists, such as para-amino clonidine (also knownas apraclonidine) and brimonidine; anti-infectives, such asciprofloxacin; non-steroidal and steroidal anti-inflammatories, such assuprofen, ketorolac, dexamethasone, rimexolone and tetrahydrocortisol;proteins; growth factors, such as EGF; and anti-allergic agents, such ascromolyn sodium, emedastine and olopatadine. Compositions of the presentinvention may also include combinations of active ingredients.

Sustained release agents include anionic polyelectrolytes, such as highmolecular weight (e.g., 50,000-6,000,000), anionic mucomimetic polymers(e.g., carboxyvinyl polymers, such as Carbopol®, and xanthan gum),polystyrene sulfonic acid polymers, cationic exchange resins (e.g.,Amberlite® or Dowex®), and the like.

The following examples are presented to illustrate further variousaspects of the present invention, but are not intended to limit thescope of the invention in any respect.

EXAMPLE 1

Ingredient Concentration (%) Betaxolol HCl 0.28 Amberlite IRP-69 0.25Carbopol 974P 0.45 Cocoyl N-Lysine* 0.03 Boric Acid 0.4  Mannitol 4.15Edetate Disodium 0.01 Tromethamine q.s. to pH 6.5 Purified Water q.s. to100 *Aminosoap LYC-12

Preparation

0.28g betaxolol hydrochloride and 0.250 grams of amberlite IRP 69 werestirred in ˜25 mL of water for ˜15 minutes. To this suspension wereadded 22.5g 2% stock slurry of Carbomer 974P, 0.40 g boric acid, 4.15 gmannitol, and 0.01 g disodium EDTA. The pH of the mixture was adjustedto ˜6.0 by the addition of 11 mL of 10% tromethamine solution followedby 30 minutes of stirring. 0.15 g Aminosoap LYC-12 (30% cocoyl N-lysine)was then added. Finally, pH is readjusted to 6.5 with 10% tromethamineand the formulation was brought to 100 g by the addition of purifiedwater.

EXAMPLE 2

Ingredient Concentration (%) Levobetaxolol HCl 0.56 Polystyrene SulfonicAcid (130 kD) 1.5  Cocoyl N-Lysine* 0.03 Boric Acid 0.35 Mannitol 3.07Edetate Disodium 0.01 NaOH and/or HCl q.s. to pH 6.5 Purified Water q.s.to 100 *Aminosoap LYC-12

EXAMPLE 3

Ingredient Concentration (%) Cocoyl N-Lysine* 0.03 Boric Acid 0.4Mannitol 4.9 Tromethamine 0.726 Edetate Disodium 0.01 Purified Waterq.s. to 100 *Aminosoap LYC-12

EXAMPLE4

Ingredient Concentration (%) Cocoyl N-Arginine* 0.03 Boric Acid 0.4Mannitol 4.9 Tromethamine 0.726 Edetate Disodium 0.01 Purified Waterq.s. to 100 *Aminosoap AR-12

EXAMPLE 5

Ingredient Concentration (%) Cocoyl N-Lysine* 0.03 Mannitol 5 PurifiedWater q.s. to 100 *Aminosoap LYC-12

EXAMPLE 6

Ingredient Concentration (%) Cocoyl N-Arginine* 0.03 Mannitol 5 PurifiedWater q.s. to 100 *Aminosoap AR-12

Comparative Example 1

Ingredient Concentration (%) Betaxolol HCl 0.28 Amberlite IRP-69 0.25Carbopol 974P 0.45 Boric Acid 0.4  Mannitol 4.5  Edetate Disodium 0.01Benzalkonium Chloride 0.01 NaOH and/or HCl q.s. to pH 6.5 Purified Waterq.s. to 100

Comparative Example 2

Ingredient Concentration (%) Benzalkonium Chloride 0.01 Mannitol 5Purified Water q.s. to 100

Comparative Example 3

Ingredient Concentration (%) Benzalkonium Chloride 0.01 Boric Acid 0.4Mannitol 4.9 Tromethamine 0.726 Edetate Disodium 0.01 Purified Waterq.s. to 100

EXAMPLE 7

Antimicrobial preservative effectiveness was determined using anorganism challenge test according to the methods described in the UnitedStates Pharmacopeia (USP) and European Pharmacopoeia (Ph.Eur.). Sampleswere inoculated with known levels of one or more of the following:gram-positive (Staphylococcus aureus ATCC 6538) and gram-negative(Pseudomonas aeruginosa ATCC 9027 and Escherichia coli ATCC 8739)vegetative bacteria, yeast (Candida albicans ATCC 10231) and mold(Aspergillus niger ATCC 10 16404). The samples were then pulled atspecified intervals to determine if the antimicrobial preservativesystem was capable of killing or inhibiting the propagation of organismspurposely introduced into the formulation. The rate or level ofantimicrobial activity determines compliance with the USP and/or Ph.Eur.preservative efficacy standards for ophthalmic preparations.

The compendial preservative standards for ophthalmic preparations arepresented below:

For Bacteria

Log Reduction of Organism Population Ph. Eur. Ph. Eur. A B Time Pull USP(Target) (Min)  6 hours — 2 — 24 hours — 3 1  7 days — — 3 14 days 3 — —28 days NI NR NI

For Fungi

Ph. Eur. Ph. Eur. A B Time Pull USP (Target) (Min)  7 days — 2 — 14 daysNI — 1 28 days NI NR NI NR = No organisms recovered NI = No increase atthis or any following time pulls — = No requirement at this time pull

The results of the microorganism challenge tests are shown in Tables 1and 2 below.

TABLE 1 Formulation USP Ph. Eur. B Ph. Eur. A Example 1 Pass Pass FailExample 2 Pass Pass Pass Comparative Example 1 Pass Fail Fail

TABLE 2 Organism (7 day results - log reduction) S. P. aeru- C. al-Formulation aureus ginosa E. coli bicans A. niger Example 3 4.8 +0.4 1.71.0 0.9 Example 4 4.8 +1.4 3.4 1.7 0.7 Example 5 4.2 +0.1 +0.1 0.7 0.3Example 6 +0.9 +1.2 +0.4 0.7 0.1 Comparative Ex. 2 4.8 4.7 4.9 4.7 2.5Comparative Ex. 3 4.8 4.7 4.9 4.7 3.7

The invention in its broader aspects is not limited to the specificdetails shown and described above. Departures may be made from suchdetails within the scope of the accompanying claims without departingfrom the principles of the invention and without sacrificing itsadvantages.

We claim:
 1. A preserved topically administrable pharmaceuticalcomposition comprising a preservative system wherein the preservativesystem consists essentially of i) at least one fatty acid/amino acidsoap having a fatty acid component derived from a C₈-C₂₄ fatty acid andan amino acid component selected from the group consisting of lysine andarginine; ii) one or more pharmaceutically acceptable antifungal acidsselected from the group consisting of boric acid; benzoic acid;salicylic acid; sorbic acid; lactic acid; acetic acid; andpharmaceutically acceptable salts thereof; and iii) one or morepharmaceutically acceptable chelating agents selected from the groupconsisting of ethylene diamine tetraacetic acid; ethyleneglycol-bis-(b-aminoethylether)-N,N,N′,N′-tetraacetic acid;1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid;ethylene-N,N′-diglycine; 2,2′-(ethylendiimino)-dibutyric acid; andpharmaceutically acceptable salts thereof.
 2. The preserved topicallyadministrable pharmaceutical composition of claim 1 wherein the fattyacid component of the fatty acid/amino acid soap is selected from thegroup consisting of cocoyl, linoleoyl, lauroyl, myristoyl, stearoyl,oleoyl, and pelargodoyl fatty acid residues.
 3. The preserved topicallyadministrable pharmaceutical composition of claim 1 wherein the amountof fatty acid/amino acid soap is from about 0.001 to about 1%.
 4. Thepreserved topically administrable pharmaceutical composition of claim 3wherein the amount of fatty acid/amino acid soap is from about 0.01 toabout 0.2%.
 5. The preserved topically administrable pharmaceuticalcomposition of claim 4 wherein the amount of fatty acid/amino acid soapis from about 0.03 to about 0.12%.
 6. The preserved topicallyadministrable pharmaceutical composition of claim 1 wherein theantifungal acid is boric acid or a pharmaceutically acceptable saltthereof.
 7. The preserved topically administrable pharmaceuticalcomposition of claim 1 wherein the amount of antifungal acid is fromabout 0.01 to about 1%.
 8. The preserved topically administrablepharmaceutical composition of claim 7 wherein the amount of antifungalacid is from about 0.1 to about 0.6%.
 9. The preserved topicallyadministrable pharmaceutical composition of claim 8 wherein the amountof antifungal acid is from 0.3 to about 0.4%.
 10. The preservedtopically administrable pharmaceutical composition of claim 1 whereinthe chelating agent is EDTA or a pharmaceutically acceptable saltthereof.
 11. The preserved topically administrable pharmaceuticalcomposition of claim 1 wherein the amount of chelating agent is fromabout 0.001 to about 1%.
 12. The preserved topically administrablepharmaceutical composition of claim 11 wherein the amount of chelatingagent is from about 0.01 to about 0.2%.
 13. The preserved topicallyadministrable pharmaceutical composition of claim 12 wherein the amountof chelating agent is from about 0.01 to about 0.1%.
 14. The preservedtopically administrable pharmaceutical composition of claim 1 whereinthe composition is selected from the group consisting of ophthalmic andotic compositions.
 15. The preserved topically administrablepharmaceutical composition of claim 1 wherein the composition furthercomprises one or more active ingredients selected from the groupconsisting of ophthalmic; dermatological; otic; and nasal agents. 16.The preserved topically administrable pharmaceutical composition ofclaim 15 wherein the composition comprises an ophthalmic agent selectedfrom the group consisting of anti-glaucoma agents; anti-infectives;non-steroidal and steroidal anti-inflammatories; proteins; growthfactors; and anti-allergic agents.
 17. The preserved topicallyadministrable pharmaceutical composition of claim 1 wherein thecomposition further comprises one or more ingredients selected from thegroup consisting of pharmaceutically acceptable buffers; tonicityagents; drug carriers; sustained-release agents; viscosity modifyingagents; comfort-enhancing agents; solubilizing aids; pH adjustingagents; antioxidants; and stabilizing agents.